Fibromyalgia syndrome (FMS) is a chronic and debilitating musculoskeletal pain disorder of unknown aetiology with usual accompanying features of fatigue, sleep disturbances and stiffness. Its place in medical textbooks was controversial with rheumatologists holding the helm of its management for many years. Over the last decade, abnormalities have been identiﬁed at multiple levels in the peripheral, central, and sympathetic nervous systems as well as the hypothalomo-pitutary-adrenal axis stress response system. With the elucidation of these pathways of pain, FMS is known more as a central sensitivity syndrome. This led to tremendous increment in interest in both pharmacological and non-pharmacological treatment of FMS. The United States Food and Drug Administration (FDA) has also successively approved 3 drugs for the management of ﬁbromyalgia – pregabalin, duloxetine and milnacipran. Non-pharmacological modalities showed aerobic exercise, patient education and cognitive behavioural therapy to be most effective. Overall, management of FMS requires a multi-disciplinary approach.
Ann Acad Med Singapore 2009;38:967-73
Key words: Aetiology, Fibromyalgia-Fibromyositis Syndromes, History, Pain syndrome
Fibromyalgia syndrome (FMS) has been referred to as a medically unexplained syndrome; a rheumatological entity described in rheumatology textbooks and taught to all training rheumatologists,and lately with newer development in research particularly in neurophysiology, as a central sensitivity syndrome. Due to its lack of objective ﬁndings on physical examination, laboratory and imaging modalities, FMS was once dismissed by physicians and the public as a psychological disorder. It was thought to be a society-driven disorder, whereby expressions of the distressed patient’s problems are made into a “disease”, hence becoming more legitimate for equal social support and sympathy from the medical community. Whether this is actual social or economic medicalisations, there are real patients suffering real symptoms.
FMS is a chronic musculoskeletal pain disorder of unknown aetiology, characterised by chronic widespread pain and muscle tenderness and the presence of tender points on examination. Patients experience both allodynia (pain from a normally nonpainful stimulus) and hyperalgesia (inappropriately intense pain from a normally painful stimulus). Other common accompanying features are fatigue, sleep disturbances, stiffness, paraesthesias, headaches, Raynaud’s like symptoms, depression and anxiety. FMS is much more than widespread pain as it overlaps substantially with other central sensitivity syndromes such as chronic fatigue syndrome, irritable bowel syndrome, chronic pelvic pain syndrome/ primary dysmenorrhoea; temporomandibular joint pain, multiple chemical sensitivity, restless legs syndrome and interstitial cystitis. In 1990, the American College of Rheumatology (ACR) published the classiﬁcation criteria of Fibromyalgia. Patients who fulﬁlled these criteria must have ﬁrstly, pain for at least 3 months involving the upper and lower body, right and left sides, as well as axial skeleton, and secondly, pain in at least 11 of 18 tender points on digital examination. The second criterion requires these tender points to be digitally palpated with about 4 kg per unit area of force. Although the criteria provided a sensitivity of nearly 88% and speciﬁcity of 81% in distinguishing FMS, it is important to exclude other causes of chronic musculoskeletal pain.
Systemic diseases, such as hypothyroidism, systemic lupus erythematosus (SLE) and malignancies, can mimic FMS and have to be excluded. The classiﬁ cation criteria initially drew considerable criticisms of over-relying on tender points, referring ﬁbromyalgia as a discrete entity rather than a cut-point along a pain-distress continuum and under- emphasising on central symptoms of the syndrome, has now gained wide recognition in the medical community. Presumably, one understands that like most ACR criteria for other rheumatic diseases, it is developed for research purpose and over the years, it has aided our understanding of FMS in both research and clinical settings.
History in Brief
Clinical description of ﬁbromyalgia has been reported since mid-1800s. In 1904, Sir William Gowers created the term “ﬁbrositis” when he was actually referring to regional pain syndrome. The term “ﬁbrositis” hence was a misnomer and no longer used as studies have shown that there were no inﬂammation within the connective tissues. “Fibromyalgia” was ﬁrst introduced in 1976 in an editorial to the section on non-articular rheumatism in the 22nd “Rheumatism Review” of the American Rheumatism Association (currently known as ACR). Derived from both Latin (ﬁ bra – ﬁ ber) and Greek words (myo-muscle and algos –pain), it literally means “pain in the muscle and ﬁbrous tissues”. Since then, the studying of ﬁbromyalgia has gathered momentum. A Medline literature review found that the total number of medical articles dealing with ﬁbromyalgia/FMS has increased 5-fold during this past decade,with non rheumatology journals publishing substantially more articles compared to a decade ago.
Fibromyalgia Syndrome and Rheumatology
Rheumatologists tend to be ambivalent about FMS though the condition has been traditionally perceived to be an entity from the rheumatology specialty due to the presence of physical pain and body tenderness. With the development of the ACR criteria in 1990 and the World Health Organization (WHO) providing Fibromyalgia ICD code, it has been conferred a “diagnosis” status. The general perception amongst rheumatologists is that patients with FMS takes up too much time for a busy clinical practice and having little success in managing these patients, most ﬁnd FMS difﬁcult to treat. Literature also showed FMS symptom measurements, such as pain, global severity, fatigue, sleep disturbance, anxiety, depression and health status, can remain unsatisfactory despite years of therapy. In the last 2 years, some even questioned whether FMS should be cared for by the rheumatologists at all as latest evidence showed FMS to be a pain syndrome centred in the nervous system. Although there was a recent study which showed that family physicians could be trained to diagnose FMS correctly in 70% of patients, there were many factors such as physician training, ethnicity and cultural biases which can affect the outcome of that study. Historical clinical evidence showed FMS can mimic autoimmune diseases, which was why its diagnosis was a constant challenge even to the rheumatologists. FMS patients can display symptoms suggestive of SLE such as peripheral neuropathy or manifest with low titre ANA levels ranging from 8.8% to 30% in FMS patients. Furthermore, FMS patients often present with bodily ache and joint pain but physical examination shows no objective evidence of synovitis. In addition, immunoglobulin depositions without complement ﬁxations in the skin were documented in the skin of FMS patients. Sicca symptoms such as dry eyes and mouth which are characteristic of Sjorgren’s syndrome has been demonstrated in FMS patients. Despite these mimics, a retrospective analysis with long-term follow-up of FMS patients however showed no increased probability of FMS patients developing into any connective tissue disease.24 Nonetheless, FMS is the second most common musculoskeletal disorder which takes up the second most amount of time in rheumatologists’ ofﬁ ces. FMS can co- exist and affect management of other rheumatic diseases. It was estimated that 20% of patients with rheumatoid arthritis and 50% of patients with SLE suffer from ﬁbromyalgia.
Local Perception of Fibromyalgia Syndrome
Local studies are however lacking. In 1999, a study in Singapore showed that ﬁbromyalgia patients exist amongst our patients. Looking into 101 patients randomly selected from medical clinics and using dolorimeter to conﬁrm the tender points, 6 patients (5.99%) fulﬁlled the ACR criteria for ﬁbromyalgia. These patients had mean tender point count of 14.17 as compared to 5.58 from a sample population. Eighteen patients (17.8%) had 11 or more tender points but did not satisfy the criteria of widespread pain of more than 3 months’ duration. A survey on the awareness and perceptions of FMS in Malaysia and Singapore showed more than 90% of rheumatologists surveyed believed that FMS is a distinct entity, an illness rather than a disease, involving medical and psychological realms, and is conﬁrmed by excluding other well-deﬁned clinical diseases through a combination of clinical evaluation and screening tests. A more recent survey (personal communication – Feng PH. Short survey on ﬁbromyalgia. August 2009) of Singapore rheumatologists/rheumatology trainees was undertaken in 2009. Although less than half responded, those responded believe FMS exists, do see FMS patients, use the ACR criteria for diagnosis, and treat FMS patients via a multi-disciplinary methods by co-managing these patients with pain specialists, psychiatrists, rehabilitation physicians, physiotherapists, psychologist and medical social workers. Majority are also of the opinion that they can play a role in managing FMS patients although some think that other specialists are more suited to managing FMS patients. Indeed, there were a few responders who believed that the diagnosis of FMS need not be a diagnosis of exclusion but it is imperative to exclude certain systemic diseases such as autoimmune diseases, malignancies or metabolic diseases. Literature evidence shows FMS patients underwent unnecessary operations thus consumed unnecessary healthcare resources. Positive diagnosis of FMS, on the other hand, is associated with reduced healthcare utilisation and reduction in investigations. Unfortunately, there is still no gold standard for diagnosis of ﬁbromyalgia. The presence of ACR criteria, however, has inadvertently made the diagnosis of ﬁbromyalgia simply to be “the blessing” of the rheumatologists.
Epidemiology of FMS
FMS is a very common condition, estimated to affect 2% to 4% of the population although local epidemiologic study is lacking. It has a prevalence of 3.4% in women versus only 0.5% in men with a female-to-male ratio of approximately 9:1. Usually diagnosed between 20 to 50 years of age, it increased with age until aged 70 after which it decreased slightly. FMS can also occur in children at prevalence rate of 1.2% and 1.4%. The prevalence of FMS is considerably higher in rheumatology clinic at 12% to 20% of new patients seen whereas it occurs in 5% to 6% of adult patients presenting at general medical and family practice clinics.
Aetiology and Pathogenesis
It is beyond the scope of this article to discuss the various aetiologies and pathogenesis of FMS. The exact aetiology of FMS is unknown and no single factor can lead to all the symptoms of FMS. Stress and medical illness can trigger FMS. Early studies showed there was no peripheral damage or inﬂ ammation within the muscles or tissues. Focus then shifted for alternative explanations. Investigations have focused upon central pain processing systems such as disturbances in neurotransmitter and neuroendocrine regulations, reduced levels of biogenic amines, increased concentrations of excitatory neurotransmitters, including substance P, and dysregulation of the hypothalamic- pituitary-adrenal axis. FMS patients experience pain differently; they have allodynia, hyperalgesia as well as lower pain threshold as compared to normal. Sleep disruption has been implicated in FMS39,40 and over 90% of FMS patients complain of sleep problem. Fibromyalgia-like symptoms were reproduced in normal volunteers by depriving them of deep sleep. Evidence using functional brain imaging allow visualisation of structures involved in pain processing further suggest central cause of pain. Patients with FMS are thought to develop functional changes in the central nervous system (CNS) that result in central pain sensitisation that is manifested as increased excitability of neurons, enlargement of their receptive ﬁelds, reduction in pain threshold and recruitment of novel afferent inputs. Abnormalities have been identiﬁed at various levels in the peripheral, central, and sympathetic nervous systems, as well as the hypothalamo-pitutary-adrenal axis stress- response system. Despite evidence that emphasises the role of sensory and CNS abnormalities for the chronic pain associated with FMS, psychosocial factors also play an important role in the development and course of FMS. These include exposure to negative life events and chronic stress, increased focus on bodily symptoms and passive pain-coping mechanisms. A recent family study also found that FMS coaggregates with mood disorders in families, suggesting the possibility of shared pathophysiologic factors in FMS and mood disorders.
Management of Fibromyalgia
Numerous literatures are available on the management of ﬁbromyalgia. Most FMS patients have been evaluated by different specialists and undergone multiple tests. The approach is to establish a correct diagnosis, to exclude differentials and to explain the implications of the diagnosis to the patients. The goals of therapy are to improve symptoms, function and emotional well-beings. Empathetic listening and acknowledgment that the patient is indeed experiencing pain would go a long way to validate the patient’s illness and establish rapport for further treatment. Prior to prescribing any form of treatment, it is imperative to assess any possible causal or perpetuating factors, including attention to psychological and sociocultural factors. Concomitant treatment of any possible nociceptive pain from an apparent pathology is important, for example, treating the pain from an inﬂ amed bursitis or degenerative spondylosis. Excessive investigations or testings if not indicated should be discouraged. Physicians are also reminded to avoid comments such as “It’s all in your mind” or “I cannot ﬁnd anything wrong with you”. Besides management of clinically relevant symptoms such as fatigue, depression, rigidity and sleep disorders; physical and emotional stress may aggravate FMS and needs to identiﬁed and treated appropriately. Evidence has shown that multi-disciplinary rehabilitation helps at least in the short term but effort needed to maintain long-term beneﬁts.
A range of medical therapeutics, such as anti-inﬂ ammatory like symptoms were reproduced in normal volunteers by depriving them of deep sleep. Evidence using functional drugs, opioids, muscle relaxants, antidepressants, sedatives and antiepileptics, have been used to treat FMS. With newer understanding of the neurophysiology of the FMS pointing to a central pain processing, research into drugs has intensiﬁed. This led to drugs being approved by the United States Food and Drug Adminstration (FDA). In June 2007, pregabalin became the ﬁrst treatment approved by the FDA for the treatment of FMS. Currently there are 3 FDA-approved drugs for FMS. They are Pregabalin (Lyrica; Pﬁ zer, Inc), Duloxetine (Cymbalta; Eli Lily and Company) and Milnacipran (Savella; Forest Laboratories and Cypress Bioscience). Market survey showed the most frequent drugs used for treatment of FMS is non-steroidal anti-inﬂammatory drugs (NSAIDS) and since FMS is largely devoid of inﬂ ammation, it is of little wonder that these treatment failed.
Alpha-2-delta ligands such as gabapentin and pregabalin were used in the treatment of many pain conditions such as painful diabetic neuropathy and postherpetic neuralgia. As a α 2δ calcium-channel antagonist that acts by limiting the neuronal release of excitatory neurotransmitters, it can decrease pain, decrease sleep latency and modify sleep architecture by improving slow-wave sleep. Pregabalin was approved by the FDA for ﬁ bromyalgia after demonstrating efﬁ cacy in 3 published trials. Generally starting at lower doses, it should reach doses such as 600 mg daily. Most patients who discontinue pregabalin do so because of somnolence and dizziness especially with higher doses. However, a meta-analysis58 showed pregabalin at 150 mg daily was generally ineffective hence higher doses (such as 300 mg, 450 mg or 600 mg) were required. Gabapentin with the same mechanism of action has also been effective in the treatment of FMS.
Anti-depressants such as tricyclic anti-depressants (TCA), selective serotonin reuptake inhibitors (SSRIs) such as ﬂuoxetine, citalopram and paroxetine as well as dual receptor inhibitors serotonin-norepinephrine reuptake inhibitors (SNRIs) have been found to be helpful in relieving symptoms of ﬁbromyalgia. However, it was the SNRIs which provide more beneﬁt as compared to pure serotonergic drugs. Initial trials with the ﬁrst available SNRI, venlafaxine, showed conﬂicting results in the management of FMS. In June 2008, another SNRI duloxetine was approved by the FDA for the management of FMS. Duloxetine was previously approved for the treatment of peripheral neuropathic pain, depression and generalised anxiety disorder. This new approval was based on data from 2 pivotal double-blind, ﬁxed-dose, randomised, phase-3 clinical trials of 12 weeks’ duration. A subsequent 6-month multi-centre, randomised, double-blind placebo-controlled trial showed reduction in pain severity and global assessments at 3 and 6 months, irrespective of depression status. The recommended dose of duloxetine is 60 mg once daily and no additional beneﬁt was observed in patients receiving 120 mg once daily. Treatment should be initiated at 30 mg once daily for 1 week to allow patients to adjust to the medication before increasing to 60 mg once daily dosing. Improvement in pain can be felt as early as the ﬁrst week and this beneﬁt persisted throughout the study period. The common side effects of duloxetine were nausea, dry mouth, constipation, decreased appetite, somnolence, hyperhidrosis and agitation.
Another SNRI, milnacipran, was approved in January 2009 for the management of ﬁbromyalgia after its efﬁcacy was established in 2 pivotal US phase 3 trials. Milnacipran was found to have greater efﬁcacy than placebo for pain relief, improvement in global well-being and physical function. The recommended dose of milnacipran is 100mg or 200 mg daily. Adverse effects of milnacipran such as nausea, headache and constipation are the main reasons for discontinuation of treatment. Milnacipran is not available in Singapore at this point of time.
In practice, patients often respond to combination of pharmacological treatments, although studies of combination pharmacotherapy are still limited. A α 2δ calcium-channel antagonist gabapentin in combination with SNRI venlafaxine was found to be more effective in improving symptoms of pain, fatigue, mood disturbance and insomnia in patients with neuropathic pain who did not respond to gabapentin monotherapy. Combinations of TCA and SSRI have also been proven more effective than either medication used alone.
Other SSRIs (ﬂuoxetine, ﬂuvoxamine, citalopram and paroxetine ) and TCA (amitriptyline, desipramine) have all been studied for treatment of FMS but most showed modest efﬁ cacy at best. A 2009 meta-analysis of 18 randomised, placebo-controlled studies of a variety of anti-depressants showed strong evidence for efﬁcacy of anti-depressants for pain relief, fatigue, depressed mood, sleep disturbance and in improving health-related quality of life.
As there is no inﬂammation present in FMS patients, anti-inﬂammatory drugs such as NSAIDS and steroids, are not effective. However, they have a role if there is concomitant inﬂammation condition which serves as a nociceptive trigger. Paracetamol helps pain relief but often insufﬁ cient when taken alone. Paracetamol in combination with tramadol, a narcotic that combines μ-opioid agonist- antagonist and SNRI activities may be helpful. Common side effects of tramadol are nausea, constipation and pruritis. However, the risk of abused and dependence with tramadol is low as compared to other opioids.
Other pharmacologic modalities included use of human growth hormone, dehydroepiandrosterone (DHEA), 5-hydroxytryptophan, topisetron and pramipexole remain under investigation. Most of these drugs attempt to combat fatigue, rigidity, insomnia or poor sleep.
Non-pharmacolgical treatment modalities, including aerobic exercises, physical therapy, cognitive behavioural therapy (CBT), massage and acupuncture can be helpful. Few of these approaches have been demonstrated to have clear-cut beneﬁ ts in randomised controlled trials.
The role of aerobic exercise has been supported by systematic review. It was postulated that aerobic exercises can stimulate endogenous analgesic systems, increase time spent in deep sleep and increase a sense of well-being and control. The challenge is to start and maintain FMS patients in a structured exercise programme and the key here is to encourage exercise according to ﬁtness level. Low impact exercise may be tailored to individuals with musculoskeletal problems.
Adjunctive CBT will be indicated for patients with prominent psychosocial stressors, and/or difﬁculty coping, and/or difﬁculty functioning. CBT has also been proven on metaanalysis to improve FMS. CBT addresses the various aspect of the biopsychosocial model of FMS and can decrease depression and pain.Patient education as a modality has been found to have therapeutic effect with patient undergoing education intervention having had signiﬁ cantly more improvement than controls but improvements are short-term. Appropriate patient selection may improve efﬁcacy. More research is needed to conﬁrm the effectiveness and to determine the best match of treatment components to particular sets of FMS symptoms.
Other modalities include acupuncture, trigger point or tender point injections, EMG-biofeedback, chiropractic or massage. There is increased interest to develop more effective non-pharmacological treatment modalities in FMS as our ability to accurately measure effect of treatment has improved. The multifaceted nature of FM suggests that multimodal individualised treatment programmes may be necessary to achieve optimal outcomes in patients with this syndrome.
Management of ﬁbromyalgia requires knowledge of its broad spectrum of symptomatology that goes beyond addressing simple complaint of pain. While diagnostic criteria do exist, they were originally developed for research purposes and need further reﬁnement as understanding of ﬁbromyalgia has evolved. Although diagnosis can be difﬁcult, new treatments, better understanding of the pathophysiology and greater involvement of different specialities can pave the way for improvement in the diagnosis of FMS. Often, a multidisciplinary healthcare setting is required to address the multidimensional nature of FMS. Outcome measures borrowed from clinical research in pain, rheumatology, neurology and psychiatry enable treatment response in speciﬁ c symptoms domains. Managing FMS patients encompass an art of practising medicine as much as knowing its scientiﬁc basis.
1. Nimnuan C, Hotopf M, Wessely S. Medically unexplained symptoms: an epidemiological study in seven specialities. J Psychosom Res 2001;51: 361-7.
2. Maiden NL, Hurst NP, Lochhead A, Carson AJ, Sharpe M. Medically unexplained symptoms in patients referred to a specialist rheumatology service: prevalence and associations. Rheumatology (Oxford) 2003;42:108-12.
3. Wolfe F, Rasker JJ. Fibromyalgia. In: Firestein GS, Budd RC, Harris E Jr, et al, editors. Firestein: Kelly’s Textbook of Rheumatology. 8th ed. Philadelphia: WB Saunders Company, 2008.
4. Yunus MB. Fibromyalgia and overlapping disorders: the unifying concept of central sensitivity syndromes. Semin Arthritis Rheum 2007;36:339-56.
5. Aceves-Avilla FJ, Ferrari R, Ramos-Remus C. New insights into culture driven disorders. Best Pract Res Clin Rheumatol 2004;18:155-71.
6. David Bradley. Disease Mongering or Medicalization? Available at: http://www.sciencebase.com/science-blog/disease-mongering-and- medicalization.html. Accessed 11 November 2009.
7. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, et al. The American College of Rheumatology 1990 criteria for the classiﬁ cation of ﬁ bromyalgia: report of the multicenter criteria committee. Arthritis Rheum 1990;33:160-72.
8. Cohen ML, Quintner JL. Fibromyalgia syndrome, a problem of tautology. Lancet 1993;342:906-9.
9. Wolfe F. The relation between tender points and ﬁ bromyalgia symptom variables: evidence that ﬁ bromyalgia is not a discrete disorder in the clinic. Ann Rheum Dis 1997;56:268-271.
10. Crofford LJ, Clauw DJ. Fibromyalgia: where are we a decade after the American College of Rheumatology classiﬁ cation criteria were developed? Arthritis Rheum 2002;46:1136-8.
11. Gowers WR. Lumbago: its lesions and analogues. BMJ 1904;1:117-21.
12. Yunus MB, Kalyan-Raman UP. Muscle biopsy ﬁ ndings in primary ﬁ bromyalgia and other forms of nonarticluar rheumatism. Rheum Dis Clin North Am 1989;15:115-34.
13. Goldenberg D. Smith N. Fibromyalgia, rheumatologists, and the medical literature: a shaky alliance. J Rheumatol 2003;30:151-3.
14. Wolfe F, Anderson J, Harkness D, Bennett RM, Caro XJ, Goldenberg DL, et al. Health status and disease severity in ﬁ bromyalgia: results of a six-center longitudinal study. Arthitis Rheum 1997;40:1571-9.
15. Shir Y, Fitzcharles MA. Should rheumatologists retain ownership of ﬁ bromyalgia? J Rheumatol 2009;36:667-70.
16. Grifﬁ ng GT. Fibromyalgia is not a rheumatology disease anymore. Medscape J Med 2008;10:47.
17. Shleryfer E, Jotkowitz A, Karmon A, Nevzorov R, Cohen H, Buskila D. Accuracy of the diagnosis of ﬁ bromyalgia by family physicians: is the pendulum shifting? J Rheumatol 2009;36:170-3.
18. Bennett RM. Confounding features of ﬁ bromyalgia syndrome: a current perspective of differential diagnosis. J Rheumatol Suppl 1989;19:58-61
19. Al-Allaf AW, Ottewell L and Pullar T. The prevalence and signiﬁ cance of positive antinuclear antibodies in patients with ﬁ bromyalgia syndrome: 2-4 years’ follow up. Clin Rheumatol 2002;21:472-7.
20. Yunus MB, Berg BC, Masi AT. Multiphase skeletal scintigraphy in primary ﬁbromyalgia syndrome: a blinded study. J Rheumatol 1989;16:1466-8.
21. Reilly PA, Littlejohn GO. Peripheral arthralgic presentation of ﬁbrositis/ ﬁbromyalgia syndrome. J Rheumatol 1992;19:281-3.
22. Caro XJ. Immunoﬂuroescent studies of skin in primary ﬁbrositis syndrome. Am J Med 1986;81(Supp 3A):43-9.
23. Bonafede RP, Downey DC, Bennett RM. An association of ﬁbromyalgia with primary Sjogren’s syndrome: a prospective study of 72 patients. J Rheumatol 1995;22:133-6.
24. Kotter I, Neuscheler D, Gunaydin I, Wernet D, Klein R. Is there a predisposition for the development of autoimmune disease in patients with ﬁbromyalgia? Retrospective analysis with long term follow up. Rheumatol Int 2007;27:1031-9.
25. Marder WD, Meenan RF, Felson DT, Reichlin M, Birnbaum NS, Croft JD, et al. The present and future adequacy of rheumatology manpower: A study of health care needs and physician supply (editorial). Arthritis Rheum 1991;34:1209-17.
26. Wolfe F, Michaud K. Severe rheumatoid arthritis (RA), worse outcomes, comorbid illness, and sociodemographic disadvantage characterize RA patients with ﬁbromyalgia. J Rheumatol 2004;31:695-700.
27. Middleton GD, McFarlin JE, Lipsky PE. The prevalence and clinical impart of ﬁ bromyalgia in systemic lupus erythematosus. Arthritis Rheum 1994;37:1181-8.
28. Mark Ng CW, Bernard Ng. Fibromyalgia in Singapore. Presented at the 19th Annual Combined Scientiﬁ c Meeting, Chapter of Physician, Academy of Medicine, Singapore; July 1999 (Published abstract).
29. Arshad A, Kong KO. Awareness and perceptions of ﬁ bromyalgia syndrome: a survey of Malaysian and Singaporean rheumatologists. Singapore Med J 2007;48:25-30.
30. Kinder AJ, Dawes PT, Clement D, Hollows C. Do patients with fibromyalgia undergo unnecessary operations? Rheumatology 2004;43(supplement 2):ii72 (Published abstract).
31. Hughes G, Martinez C, Myon E, Taïeb C, Wessely S. The impact of a diagnosis of ﬁ bromyalgia on health care resource use by primary care patients in the UK: an observational study based on clinical practice. Arthritis Rheum 2006;54:177-83.
32. Annemans L, Wessely S, Spaepen E, Caekelbergh K, Caubère JP, Le Lay K, et al. Health economic consequences related to the diagnosis of ﬁ bromyalgia syndrome. Arthritis Rheum 2008;58:895-902.
33. Wolfe F, Ross K, Anderson J, Russell IJ, Herbert L. The prevalence and characteristics of ﬁ bromyalgia in the general population. Arthritis Rheum 1995;38:19-28.
34. Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo R, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum 2008;58:26-35.
35. Buskila D, Press J, Gedalia A, Klein M, Neumann L, Boehm R, et al. Assessment of nonarticular tenderness and prevalence of ﬁ bromyalgia in children. J Rheumatol 1993;20:368-70.
36. Buskila D, Neumann L, Hershman E, Gedalia A, Press J, Sukenik S. Fibromyalgia syndrome in children – an outcome study. J Rheumatol 1995;22:525-8.
37. Wolfe F, Cathey MA. Prevalence of primary and secondary ﬁ brositis. J Rheumatol 1983;10:965-8.
38. Yunus MB, Masi AT, Calabro JJ, Miller KA, Feigenbaum SL. Primary ﬁbromyalgia (ﬁbrositis): clinical study of 50 patients with matched normal controls. Semin Arthritis Rheum 1981;11:151-71.
39. Moldofsky H, Scarisbrick P, England R and Smythe H. Musculoskeletal symptoms and non-REM sleep disturbance in patients with “ﬁbrositis syndrome” and healthy subjects. Psychosom Med 1975;37:341-51.
40. Moldofsky H, Scarisbrick P. Induction of neurasthenic musculoskeletal pain syndrome by selective sleep stage deprivation. Psychosom Med 1976;38:35-44.
41. Gracely RH, Petzke F, Wolf JM, Clauw DJ. Functional magnetic resonance imaging evidence of augmented pain processing in ﬁbromyalgia. Arthritis Rheum 2002;46:1333-43.
42. Cook DB, Lange G, Ciccone DS, Liu WC, Steffeer J, Natelson BH. Functioning imaging of pain in patients with primary ﬁ bromyalgia. J Rheumatol 2004;31:364-78.
43. Gibson SJ, Littlejohn GO, Gorman MM, Helme RD, Granges G. Altered heat pain thresholds and cerebral event-related potentials following painful CO2 laser stimulation in subjects with ﬁ bromyalgia syndrome. Pain 1994;58:185-93.
44. Abeles AM, Pillinger MH, Solitar BM, Abeles M. Narrative review: the pathophysiology of ﬁbromyalgia. Ann Intern Med 2007;146:726-34.
45. Clauw DJ, Chrousos GP. Chronic pain and fatigue syndromes: overlapping clinical and neuroendocrine features and potential pathogenic mechanisms. Neuroimmunomodulation 1997;4:134-53.
46. Arnold LM, Hudson JI, Keck PE, Auchenbach MB, Javaras KN, Hess EV. Comorbidity of ﬁ bromyalgia and psychiatric disorders. J Clin Psychiatry 2006;67:1219-25.
47. Goldenberg DL, Burckhardt C, Crofford L. Management of ﬁbromyalgia syndrome. JAMA 2004;292:2388-95.
48. Carville SF, Arendt-Nielsen S, Bliddal H, Blotman F, Branco JC, Buskila D, et al. EULAR evidence-based recommendations for the management of ﬁ bromyalgia syndrome. Ann Rheum Dis 2008;67:536-41.
49. Boomershine CS, Crofford LJ. A symptom-based approach to pharmacologic management of ﬁ bromyalgia. Nat Rev Rheumatol 2009; 5:191-9.
50. Burckhardt CS, Goldenberg D, Crofford LJ, Gerwin R, Gowans S, Jackson K, et al. Fibromyalgia Syndrome Pain Management Guideline Panel 2002-2005. Guideline for the management of ﬁ bromyalgia pain in adults and childrens: APTS Clinical Practice 2005 Guideline Series, No 4. Glenview, IL: American Pain Society.
51. Wood PB. Treating comorbidities in ﬁ bromyalgia. Pain Pract 2008;18: 42-53.
52. Karjalainen KA, Malmivaara A, van Tulder M, Roine R, Jauhiainen M, Hurri H, et al. Multidisciplinary rehabilitation for ﬁbromyalgia and musculoskeletal pain in working age adults. Cochrane Database Syst Rev 2000;2:CD001984.
53. Hauser W, Bernardy K, Arnold B, Offenbacher M, Schiltenwolf M. Efﬁcacy of multicomponent treatment in ﬁbromyalgia syndrome: a meta-analysis of randomized controlled clinical trials. Arthritis Rheum 2009;61:216-24.
54. Rooks DS. Fibromyalgia treatment update. Curr Opin Rheumatol 2007;19:111-7.
55. Arnold LM, Russell IJ, Diri EW, Duan WR, Young JP Jr, Sharma U, et al. A 14-week, randomized, double-blinded, placebo-controlled monotherapy trial of pregabalin in patients with ﬁbromyalgia. J Pain 2008;9:792-805.
56. Crofford LJ, Rowbotham MC, Mease PJ, Russell IJ, Dworkin RH, Corbin AE, et al. Pregabalin for the treatment of ﬁ bromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2005;52:1264-127.
57. Mease PJ, Russell IJ, Arnold LM, Florian H, Young JP Jr, Martin SA, et al. A randomized, double-blind, placebo-controlled, phase III trial of pregabalin in the treatment of patients with ﬁ bromyalgia. J Rheumatol 2008;4:514-5.
58. Moore RA, Straube S, Wiffen PJ, Derry S, McQuay HJ. Pregabalin for acute and chronic pain in adults. Cochcrane Database Syst Rev 2009;(3):CD007076.
59. Arnold LM, Goldenberg, DI, Stanford SB, Lalonde JK, Sandhu HS, Keck PE Jr, et al. Gabapentin in the treatment of ﬁ bromyalgia: a randomized, double-blind, placebo-controlled, multicenter trial. Arthritis Rheum 2007;56:1336-44.
60. Sayar K, Aksu G, Ak I, Tosun M. Venlafaxine treatment of ﬁbromyalgia. Ann Pharmacother 2003;37:1561-5.
61. Arnold LM, Lu Y, Crofford LJ, Wohlreich M, Detke MJ, Iyengar S, et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of ﬁbromyalgia patients with or without major depressive disorder. Arthritis Rheum 2004;50:2974-84.
62. Arnold LM, Rosen A, Pritchett YL, D’Souza DN, Goldstein DJ, Iyengar S, et al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with ﬁ bromyalgia with or without major depressive disorder. Pain 2005;119:5-15.
63. Russell IJ, Mease PJ, Smith TR, Kajdasz DK, Wohlreich MM, Detke MJ, et al. Efﬁ cacy and safety of duloxetine for treatment of ﬁbromyalgia in patients with or without major depressive disoders: Results from a 6-month, randomized, double-blind, placebo-controlled, ﬁxed-dose trial. Pain 2008;136:432-44.
64. Vitton O, Gendreau M, Gendreau J, Kranzler J, Rao SG. A double-blind placebo-controlled trial of milnacipran in the treatment of ﬁ bromyalgia. Hum Psychopharmacol 2004;19(Suppl 1):S27-35.
65. Clauw DJ, Mease P, Palmer RH, Gendreau RM, Want Y. Milnacipran for the treatment of ﬁ bromyalgia in adults: a 15-week, multicenter, randomized, double-blind, placebo-conrolled, multiple-dose clinical trial. Clin Ther 2008;30:1988-2004.
66. Mease PJ, Clauw DJ, Gendreau RM, Rao SG, Kranzler J, Chen W, et al. The efﬁ cacy and safety of minacipran in the treatment of ﬁ bromyalgia: a randomized, double-blind, placebo-controlled trial. J Rheumatol 2009;36:398-409.
67. Simpson DA. Gabapentin and venlafaxine for the treatment of painful diabetic neuropathy. J Clin Neuromuscul Dis 2001;3:53-62.
68. Goldenberg DL, Mayskiy M, Mossey CJ, Ruthazer R, Schmid C. A randomized, double-blind crossover trial of ﬂ uoxetine and amitriptyline in the treatment of ﬁ bromyalgia. Arthritis Rheum 1996 ;39:1852-9.
69. Hauser W, Bernardy K, Uceyler N, Sommer C. Treatment of ﬁbromyalgia syndrome with antidepressants: a meta-analysis. JAMA 2009;301: 198-209.
70. Bennett RM, Kamin M, Karim R, Rosenthal N. Tramadol and acetaminophen combination tablets in the treatment of ﬁ bromyalgia pain: a double-blind, randomized, placebo-controlled study. Am J Med 2003;114:537-45.
71. Busch AJ, Thille P, Barber KA, Schachter Cl, Bidonde J, Collacott BK. Best practice: E-Model – prescribing physical activity and exercise for individuals with ﬁbromyalgia. Physiother Therory Pract 2008;24:151-66.
72. Janal MN. Pain sensitivity, exercise and stoicism. J R Soc Med 1996;89:376-381.
73. McCain GA, Bell DA, Mai FM, Halliday PD. A controlled study of the effects of a supervised cardiovascular ﬁ tness training program on manifestations of primary ﬁ bromyalgia. Arthritis Rheum 1988;31: 1135-41.
74. Arnold LM. Biology and therapy of ﬁ bromylagia. New therapies in ﬁ bromyalgia. Arthritis Res Ther 2006:8:212.
75. Morley S, Eccleston C, Williams A. Systematic review and meta-analysis of randomized controlled trials of cognitive behavior therapy and behaviour therapy for chronic pain in adults, excluding headache. Pain 1999;80:1-13.
76. Williams DA. Psychological and behavioral therapies in ﬁbromyalgia and related syndromes. Best Pract Res Clin Rheumatol 2003;17:649-65.
77. Hammond A, Freeman K. Community patient education and exercise for people with ﬁbromyalgia: a parallel group randomized controlled trial. Clin Rehabil 2006;20:835-46.
78. Bennet RM. The rational management of ﬁbromyalgia patients. Rheum Dis Clin North Am 2002;28:181-99.
Chong YY, Ng BY. Ann Acad Med Singapore. 2009 Nov;38(11):967-73.